With rapid advances in genomics, the next major undertaking is to determine the structure and function of the proteins encoded by newly discovered genes. However, current predictive ability for protein structure is limited, in part because the factors that define a single low energy fold are not yet well understood. Protein de novo design has demonstrated that simple binary coding of hydrophobic and hydrophilic residues is too simplistic a model to define a native-like structure. To gain insight into the factors that contribute to specificity in protein folding, we are investigating the ability of interactions of polarized C-H groups with aromatic rings to provide specificity to protein structure through weakly polar "hydrophobic" interactions. In proteins, this type of interaction includes, for example, edge-face interactions between two aromatic sidechains, the interaction of a lysine sidechain with an aromatic group, and the interaction of the axial hydrogens of carbohydrates with the x-cloud of an aromatic ring in carbohydrate binding proteins. We expect that these C-H...( interactions would provide stability and specificity to protein structure because the interaction consists of an electrostatic interaction between the electron-poor C-H and the x-cloud of the aromatic ring, in addition to hydrophobic and van der Waals components. We will investigate the nature of these interactions in model B-hairpin peptides and determine their impact on specificity of strand register in B-hairpins. Subsequently, we will determine their effect on folding of the protein ubiquitin, which has been shown to fold via the nucleation of a B-hairpin.